ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme)
| PDB rendering based on 1bkc.
| Available structures: 1bkc, 1zxc, 2a8h, 2ddf, 2fv5, 2fv9, 2i47
|| ADAM17; CD156b; MGC71942; TACE; cSVP
| External IDs
|| OMIM: 603639 MGI: 1096335 Homologene: 2395
| Molecular Function:
|| • metalloendopeptidase activity|
• protein binding
• zinc ion binding
• metal ion binding
| Cellular Component:
|| • cytoplasm|
• integral to plasma membrane
| Biological Process:
|| • proteolysis|
• Notch signaling pathway
• cell-cell signaling
| RNA expression pattern
More reference expression data
|| NM_003183 (mRNA)|
|| Chr 2: 9.55 - 9.61 Mb
|| Chr 12: 21.57 - 21.62 Mb
| Pubmed search
ADAM metallopeptidase domain 17 (ADAM17), also called TACE, is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases.
Additional recommended knowledge
ADAM17 is a 824 amino acid polypeptide.
Enzymes in this family are transmembrane glycoproteins that are characterized by their conserved, multi-domain structure.
ADAM17 is understood to be involved in the processing of tumor necrosis factor alpha (TNF-α) at the surface of the cell, and from within the intracellular membranes of the trans-Golgi network. This process, which is also known as 'shedding', involves the cleavage and release of a soluble ectodomain from membrane bound pro-proteins (such as pro-TNF-α), and is of known physiological importance. ADAM17 was the first 'sheddase' to be identified, and is also understood to play a role in the release of a diverse variety of membrane-anchored cytokines, cell adhesion molecules, receptors, ligands and enzymes.
Interactions between ADAM17 and pro-TNF-α
Cloning of the TNF-α gene revealed it to encode a 26kDa type II transmembrane pro-polypeptide that becomes inserted into the cell membrane during its maturation. At the cell surface, pro-TNF-α is biologically active, and is able to induce immune responses via juxtacrine intercellular signaling. However, pro-TNF-α can undergo a proteolytic cleavage at its Ala76-Val77 amide bond, which releases a soluble 17kDa extracellular domain (ectodomain) from the pro-TNF-α molecule. This soluble ectodomain is the cytokine commonly known as TNF-α, which is of pivotal importance in paracrine signaling. This proteolytic liberation of soluble TNF-α is catalyzed by ADAM17.
Interactions between ADAM17 and L-selectin
ADAM17 has a role in the shedding of l-selectin, a cellular adhesion molecule.
Cellular Localization of ADAM17
The localization of ADAM17 is speculated to be an important determinant of shedding activity. TNF-α processing has classically been understood to occur in the trans-Golgi network, and be closely-connected to transport of soluble TNF-α to the cell surface. However, research exists that suggests that the majority of mature, endogenous ADAM17 may be localized to a perinuclear compartment, with only a small amount of TACE being present on the cell surface. The localization of mature ADAM17 to a perinulcear compartment therefore raises the possibility that ADAM17-mediated ectodomain shedding may also occur in the intracellular environment, in contrast with the conventional model.
ADAM17 as a target for future medicines?
Since TNF-α is a potent and pivotal mediator in the inflammatory process, considerable investment has been made in the research into- and development of anti-TNF-α agents, for the purpose of reducing the severity of inflammatory responses in disease states (e.g. the medicine Etanercept for treatment of rheumatoid arthritis). The inhibition of ADAM17 by a pharmacological agent may represent another means by which the effects of TNF-α can be modulated, although this is yet to be demonstrated clinically in humans.
Functional ADAM17 has been documented to be ubiquitously expressed in the human colon, with increased activity in the colonic mucosa of patients with ulcerative colitis, a main form of inflammatory bowel disease. These data will no doubt contribute to growing interest in the inhibition of ADAM17 as a potential therapeutic strategy.
Other points of interest
Recent in vitro experiments have provided evidence that suggests that ADAM17 may play a prominent role in the Notch signaling pathway, during the proteolytic release of the Notch intracellular domain (from the Notch1 receptor) that occurs following ligand binding. Other experiments have also suggested that expression of ADAM17 may be inhibited by ethanol.
- ^ Black R, Rauch C, Kozlosky C, Peschon J, Slack J, Wolfson M, Castner B, Stocking K, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley K, Gerhart M, Davis R, Fitzner J, Johnson R, Paxton R, March C, Cerretti D (1997). "A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells". Nature 385 (6618): 729-33. PMID 9034190.
- ^ http://www.jleukbio.org/cgi/reprint/72/6/1142.pdf
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- Lum L, Wong BR, Josien R, et al. (1999). "Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival.". J. Biol. Chem. 274 (19): 13613-8. PMID 10224132.
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- Nelson KK, Schlöndorff J, Blobel CP (2000). "Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta.". Biochem. J. 343 Pt 3: 673-80. PMID 10527948.
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- Lee MH, Verma V, Maskos K, et al. (2002). "The C-terminal domains of TACE weaken the inhibitory action of N-TIMP-3.". FEBS Lett. 520 (1-3): 102-6. PMID 12044879.
- Díaz-Rodríguez E, Montero JC, Esparís-Ogando A, et al. (2002). "Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding.". Mol. Biol. Cell 13 (6): 2031-44. doi:10.1091/mbc.01-11-0561. PMID 12058067.
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